As it is known in the art, in order to get uniform acceptable tablets, the bulk to be tabletted must be homogeneous, does not segregate during tabletting process and must have good flow-ability properties. This is the most common reason why the granulation is used.
Depending on the quality of the API and on the used excipients, the granulation regards all the bulk to be tabletted (except the lubricants, which have generally to be added apart) or only a part of the materials used in the formulation.
Not many years ago the most used granulation system was the so called wet granulation.
Wet granulation (e.g. fluid bed granulation or granulation in a high shear mixer) requires the use of water and/or alcohol and (especially in the old times) the use of substances like methanol, isopropanol, methylene choride etc.
The results of wet granulations were (and still are) often very good from the point of view of reduction of dust and bulk size, granules flow-ability, bulk homogeneity. Sometimes, even the compressibility of the bulk into tablets has improved very much thanks to the wet granulation techniques.
However, serious problems could become visible with the stability of some wet processes (which means also difficulties in the validation of the processes) and with the quality of the tablets (shelf-life, hardness, disintegration time and so on). This is also because the final moisture content of the granulated bulk is often different from the total moisture content of the non granulated bulk. Furthermore, the results (quality of the granules: flow-ability, homogeneity, porosity and particle size distribution) for small batches (pilot-batches) are often different from the results of the production batches. This derives from the fact that it is very difficult to scale-up a wet granulation process, due to the number of parameters which have influence on the results of the granulation.
A tablet formulation, where the dry bulk (i.e. API and excipients) can be compressed into tablets without previous granulation, is a target and a challenge for the Pharmaceutical industry. In fact such so called direct compression process is theoretically the best possible (above all for economical reasons). However the direct compression is not applicable to many processes, due especially to the fact that many times the APIs are composed of very small and badly flowing particles while the excipients can have a good flow-ability. This fact can cause segregation at the tabletting stage.
When direct compression is not possible or difficult to handle, dry granulation is a valid alternative.
A dry granulation process is described in the art as a method where the powders to be granulated are first mixed (if necessary) and then densified e.g.—in the case of roll compaction—by passing them between two rotating rolls. The ribbons or flakes resulting from such compaction are then broken into granules by passing the ribbons/flakes through a flake breaker and/or through a sieve granulator.
A lot of devices have been created in order to feed homogeneously the compaction rollers or other densification devices, to avoid the formation of dust in the sieve granulator, to control the compaction force, in order to have an uniform ribbon, and to avoid an over compaction (which can have a bad influence also on the dissolution rate of the tablets . . . ) etc. Nevertheless, as result of a normal dry granulation (for instance roll compaction), the produced granulated bulk is not generally homogeneous, because of the contemporary presence in it of big (1-2 mm of diameter) depending on the size of the sieve openings in the sieve granulator) and sometimes dense granules together with very small (a few micrometers of diameter) light particles. This fact, which is mostly a natural consequence of the flake breaking and/or granulating process, causes a bad flow-ability of the material and segregation (i.e. the more dense granules flow faster than the less dense) of the bulk during tabletting phase, with the result of rejecting complete batches, because of the bad uniformity content of the tablets.
To overcome the above mentioned problems, related to the dry granulation, in the art there are known some technical devices where the small/fine particles and sometimes also the most big particles produced in a normal roll compaction system (i.e. compactor and sieve granulator) are separated mechanically from the rest of the granules with the help of vibrating screen(s). This separation process is generally complicated (big sized sieves are generally needed), noisy and full of problems. In fact, it is very difficult to use, in a screen separator, a sieve whose openings are smaller than for instance 500 μm of diameter. This is because—due to well known physical phenomena—, the granulated material has (more or less, depending on the material) an adhering tendency which can often cause the obstruction of the sieve openings, arresting all the process or deteriorating the quality of the produced bulk.
An example of vibrator screens is the one indicated in the US Patent 20030187167 (see FIG. 1A).
As it is evident in the figure, the oversized particles and the fines are collected and transported to be compacted and dry granulated again. For separating the product (i.e. the good particles from the oversized and from the fines), vibrations are needed. The process can be continuous, when new material is continuously added to the particles to be recycled and if the sieve openings are not blocked. The recycling system of the FIG. 1A consists in mechanical horizontal and vertical screws.
Instead of using vibrating screen separators, one can separate the fine dusty particles from the acceptable granules with the help of a gas stream.
One example of this separation is disclosed in Patent WO 99/11261, where a Minox sieve type MTS 1 200 equipped with an air jet system is used. The air is escaping upwards from a rotating perforated blade fixed horizontal under the sieve. By this action the fine particles are blown off from the coarse particles and sucked downwards through the sieve to the receiver by the action of an under pressure.
Such kind of particle separation can be applied to a compaction process, by placing the Minox apparatus under the sieve granulator, where the flakes/ribbons are broken into granules and passed through a screen. In this case, the screen of the sieve granulator must have opening dimensions that represent the maximum dimension size of the acceptable particles. The apparatus will collect the “acceptable” granules while the very small particles can be “recycled” by conveying them pneumatically (i.e. via air stream) or mechanically to be compacted again. In Patent WO 99/11261 the minimum size of the acceptable particles is indicated in 125 μm. This means that the openings of the screen of the Minox apparatus are sized 125 μm. The maximum size of the particles is indicated between 2.0 and 1.0 mm. As indicated in the Patent WO 99/11261, the sieve applied in the above mentioned Minox apparatus has a pretty big diameter (120 cm), if the granulation of Amoxicillin trihydrate powder is carried out with a roller compactor type Chilsonator 4L×10D (diameter of rolls: 25.4 cm) and the applied roll pressure is 1100 psi.
The results of the above mentioned air separation seem to be very much related to the quality of the material to be granulated and to the compaction pressure, while the efficiency of the process (i.e. the quantity of product per hour) can be also influenced from the dimensions of the openings of the screen, from the diameter of the screen and from the quantity of the air passing through the screen. Problems can be predicted with sticky materials, and/or when the openings of the screen are too little and/or the diameter of the screen is not big enough and/or when the applied roll pressure is very little.
Another example of air separation is indicated in Patent GB 1567204, where dusty particles mixed with air are introduced tangentially in a guide helix of a cylindrical hollow body and are guided along the wall of a cylindrical surface on an air cushion. The fine material leaves the cylindrical hollow body axially via discharge pipes whereas the coarse material occurs in the coarse material discharge pipe (see FIG. 1B). As it is evident in the figure, in Patent GB 1567204 the cylindrical surface (4) is equipped with discharge openings (3) into which air is guided from fluid inflow pipes (1) via a distribution chamber (2). The final material leaves the cylindrical hollow body (5) axially via discharge pipes (8) for fluidised material, whereas the coarse material occurs in the coarse material discharge pipe (9).
Even Patent WO 2008/056021 provides a dry granulation method where the fine particles are separated from the granules by entering the fine particles in a gas stream. According to such patent, the gas stream may be directed through a fractioning chamber and separates at least some fine particles from the granules. The fine particles may then be returned to the system for immediate re-processing or they may be placed into a container for later re-processing. The fractioning chamber described in Patent WO 2008/056021 may comprise means to guide a gas stream into the fractioning means, means to put the compacted mass into motion and means to guide removed fine particles entrained in the gas stream from the fractioning means, e.g. for re-processing. One of the drawings presented in the patent is the one presented in FIG. 10 of the present application: the separation of granules from fines is produced in a cylindrical surface (401), equipped with openings and guide helix. The material is introduced from the opening (405), the fines go out from opening (409) and the granules leave the chamber via discharge pipe (407). Air is coming from the opening (406) and leaves the chamber from opening (408). As explained in the same patent, “instead of relying on the mesh size in the sieving, the fractioning device of the invention relies on the gas stream's ability to entrain fine particles from the moving compacted mass. The determination of the size of acceptable granules is achieved by balancing their gravitational force (together with other forces, e.g. mechanical and centrifugal forces) against the force of the gas stream”. In such separation system, the direction of the flow of the gas stream must have a component which is contrary to that of the direction of flow of the compacted mass.
The quality of the granules obtained in a dry granulation process where gas separators are used is generally supposed to be good under the aspect of flow-ability and of the homogeneity of the produced bulk. Particularly, in Patent WO 99/11261 is presented a process which, between other advantages “allows for disintegration of dosage forms into primary drug particles followed by a high dissolution rate because no binders have been used”. In Patent WO 2008/056021 is presented a process where the porosity of the granules (obtained mostly using low compaction pressures) is supposed to have a very relevant importance for the disintegration and the tensile strength of the tablets. In the same Patent WO 2008/056021 it is asserted (Page 23, 4-6) that the patent provides tablets which “may have at least two or three of the following properties: high tensile strength, high drug load, low amount of lubricant, quick disintegration time and insensitivity to storage time”.
According to the same Patent WO 2008/056021, the product of the process of the invention is influenced by triboelectric phenomena, with the final effect of an enlargement of the granules. In Patent WO 2008/056021 such agglomeration phenomena are supposed to happen in the fractioning device and are due to the fact that the carrier gas flows in a direction that is different from the flow of accepted granules (Patent WO 2008/056021, page 42, 19-24, page 43, 21-22 and page 44, 1-2).
When the gas is used in the prior art and in a dry granulation system (described e.g. in the above mentioned Patent WO 99/11261 and Patent WO 2008/056021) for getting granules of better flow-ability, better porosity and, in some particular cases, of a larger size, the quantity of the gas to be used must evidently be regulated following parameters which are mostly related to the density of the material to be processed and to the structure of the system (e.g. sieve dimension, compaction force, efficiency of the granulator etc.). It is very evident that the required quantity of the gas to be used in the above mentioned air separator systems must be chosen “a posteriori”, after some experiments and taken into account all the other parameters used in the granulation, e.g. the density of the granules and the efficiency of the system. Every variation of the quantity of the used gas can create lack of balance in the granulation system, with consequences e.g. on the homogeneity of the granulated bulk, on the porosity of the granules, on the efficiency of all the system and on the flow-ability of the bulk. For this reason no one of the dry granulation methods presented in the actually known prior art is defining the quantity of the gas to be used in a granulation process as a parameter to be chosen “a priori”, i.e. as the most important parameter from which depends the choose of the other granulation parameters.
The direction of the gas stream is also taken into account, in the prior art, for the only purpose of getting granulation results that guaranty mostly the homogeneity of the granulated bulk, the porosity of the granules, the efficiency of all the system and on the flow-ability of the bulk.
The phenomena related to a gas stream which carries up a powdered bulk (e.g. triboelectrification phenomena) are generally considered in a negative way, due mostly to the risks of explosions and to the apparent necessity of avoiding the possible creation of granules electrically charged (which could have bad influence on the flow-ability of the product). Triboelectrification can anyhow enhance the enlargement of the granules, as indicated in Patent WO 2008/056021.
According to the inventor of this invention, the phenomena related to a gas stream which carries up a powdered bulk can have many positive effects on the final quality of the granules, above all from the point of view of the disintegration of granules and tablets and on the bioavailability of the tablets. Such positive effects can be obtained with an innovative granulation system, where the quantity and the direction of the gas are strictly controlled and are considered the very important parameters in the system. Due to the importance of the gas stream in this invention, we can define this innovative granulation system as an “Aerodynamic granulation system”.
Essentially contrary to what is taught in Patent WO 2008/056021, according to the present invention the enlargement of the granules, due to the triboelectric effects, does not take part only or above all in the fractioning device and does not depend essentially from the fact that the carrier gas flows in a direction that is different from the flow of the accepted granules. The inventor believes that such granules enlargement takes part potentially in every part of the apparatus, which is in contact with gas, and reaches its final status when the produced bulk is mixed up, after the end of the dry granulation process. Also according to this invention triboelectric effects can be controlled, when necessary, with the help of an electromagnetic field.
Also, basically differently to what is taught in Patent WO 2008/056021, according to this invention the porosity of the granules is enhanced from the fact that the powders entering the compaction chamber are electrically charged. This means that the compaction pressure, even if regulated a bit higher than necessary in a normal process, may produce a ribbon which is suitable for producing porous granules at the granulation stage.
The porosity of the granules are also enhanced from the fact that—contrary to what is needed in Patent WO 2008/056021—in an apparatus conform to the present invention the gas stream enters also the compaction chamber, as well as the granulator device.
According to the present invention, many important qualities of the manufactured granules and of the tablets, produced from a bulk obtained in a production method conform to the present invention, are directly related to the quantity of the gas used in the granulation stage. Such qualities concern mostly the disintegration of the granules into water, the hardness of the tablets, and also the bioavailability of the tablets.